Current Advances in Pharmacotherapy and Technology for...
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Review Article Current Advances in Pharmacotherapy and Technology for Diabetic Retinopathy: A Systematic Review Lei Lu , 1 Ying Jiang, 1 Ravindran Jaganathan , 2 and Yanli Hao 3 1 Department of Ophthalmology, Yan’an People’s Hospital, Qilipu St., Baota Qu, Yan’an, Shaanxi 716000, China 2 Pathology Unit, Lab Based Department, Faculty of Medicine, Royal College of Medicine Perak, Universiti Kuala Lumpur, No. 3, Jalan Greentown, 30450 Ipoh, Perak, Darul Ridzuan, Malaysia 3 Department of Ophthalmology, Yan’an People’s Hospital, Bei Da Jie, Baota Qu, Yan’an, Shaanxi 716000, China Correspondence should be addressed to Yanli Hao; [email protected] Received 19 July 2017; Revised 12 October 2017; Accepted 7 November 2017; Published 17 January 2018 Academic Editor: Hyeong Gon Yu Copyright © 2018 Lei Lu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Diabetic retinopathy (DR) is classically defined by its vascular lesions and damage in the neurons of the retina. The cellular and clinical elements of DR have many features of chronic inflammation. Understanding the individual cell-specific inflammatory changes in the retina may lead to novel therapeutic approaches to prevent vision loss. The systematic use of available pharmacotherapy has been reported as a useful adjunct tool to laser photocoagulation, a gold standard therapy for DR. Direct injections or intravitreal anti-inflammatory and antiangiogenesis agents are widely used pharmacotherapy to effectively treat DR and diabetic macular edema (DME). However, their effectiveness is short term, and the delivery system is often associated with adverse effects, such as cataract and increased intraocular pressure. Further, systemic agents (particularly hypoglycemic, hypolipidemic, and antihypertensive agents) and plants-based drugs have also provided promising treatment in the progression of DR. Recently, advancements in pluripotent stem cells technology enable restoration of retinal functionalities after transplantation of these cells into animals with retinal degeneration. This review paper summarizes the developments in the current and potential pharmacotherapy and therapeutic technology of DR. Literature search was done on online databases, PubMed, Google Scholar, clinitrials.gov, and browsing through individual ophthalmology journals and leading pharmaceutical company websites. 1. Introduction Diabetic Mellitus (DM), a chronic metabolic disorder, is a major public health problem due to its associated complica- tions [1]. One of the major complications of DM is DR, which is an important cause of preventable blindness. In the United States, DR is the leading cause of blindness for patients with age of 20 to 64 and accounts for about 12% of all new cases [2]. Moreover, 80% of patients with DM for more than 20 years are most commonly diagnosed with DR. Nonetheless, at least 90% of new cases were shown to have retinal structure and function restoration when proper treatments were applied [3]. DR is characterized by the progressive damage in the ret- inal microvasculature. It can be classified into nonprolifera- tive DR (NPDR) and proliferation DR (PDR) [4, 5]. NPDR is featured with intraretinal microvasculature changes [6] and can be further divided into mild, moderate, and severe stages that may associate with diabetic macular edema (DME) [7]. PDR involves the formation and growth of new blood vessels (retinal neovascularization) in low oxygen con- dition [6]. Thus, the newly formed blood vessels are fragile and without timely treatment may lead to vision loss. In most cases, DR is also featured with increased vascular permeabil- ity, leading to fluid accumulation and retinal hemorrhages in the macula, all of which referred to DME [8–10]. There are three major treatments of DR, such as laser sur- gery, pharmacotherapy, and vitrectomy, which are effective to reduce vision impairment [11]. Intraocular pharmacother- apy, particularly applying anti-inflammatory (corticoste- roids) and anti-angiogenic agents (VEGF inhibitors), has become the most preferred therapy for DR [12]. The Hindawi Journal of Ophthalmology Volume 2018, Article ID 1694187, 13 pages https://doi.org/10.1155/2018/1694187
Transcript of Current Advances in Pharmacotherapy and Technology for...
Review ArticleCurrent Advances in Pharmacotherapy and Technology forDiabetic Retinopathy: A Systematic Review
Lei Lu ,1 Ying Jiang,1 Ravindran Jaganathan ,2 and Yanli Hao 3
1Department of Ophthalmology, Yan’an People’s Hospital, Qilipu St., Baota Qu, Yan’an, Shaanxi 716000, China2Pathology Unit, Lab Based Department, Faculty of Medicine, Royal College of Medicine Perak, Universiti Kuala Lumpur, No. 3,Jalan Greentown, 30450 Ipoh, Perak, Darul Ridzuan, Malaysia3Department of Ophthalmology, Yan’an People’s Hospital, Bei Da Jie, Baota Qu, Yan’an, Shaanxi 716000, China
Correspondence should be addressed to Yanli Hao; [email protected]
Received 19 July 2017; Revised 12 October 2017; Accepted 7 November 2017; Published 17 January 2018
Academic Editor: Hyeong Gon Yu
Copyright © 2018 Lei Lu et al. This is an open access article distributed under the Creative Commons Attribution License, whichpermits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Diabetic retinopathy (DR) is classically defined by its vascular lesions and damage in the neurons of the retina. The cellular andclinical elements of DR have many features of chronic inflammation. Understanding the individual cell-specific inflammatorychanges in the retina may lead to novel therapeutic approaches to prevent vision loss. The systematic use of availablepharmacotherapy has been reported as a useful adjunct tool to laser photocoagulation, a gold standard therapy for DR. Directinjections or intravitreal anti-inflammatory and antiangiogenesis agents are widely used pharmacotherapy to effectively treat DRand diabetic macular edema (DME). However, their effectiveness is short term, and the delivery system is often associated withadverse effects, such as cataract and increased intraocular pressure. Further, systemic agents (particularly hypoglycemic,hypolipidemic, and antihypertensive agents) and plants-based drugs have also provided promising treatment in the progressionof DR. Recently, advancements in pluripotent stem cells technology enable restoration of retinal functionalities aftertransplantation of these cells into animals with retinal degeneration. This review paper summarizes the developments in thecurrent and potential pharmacotherapy and therapeutic technology of DR. Literature search was done on online databases,PubMed, Google Scholar, clinitrials.gov, and browsing through individual ophthalmology journals and leading pharmaceuticalcompany websites.
1. Introduction
Diabetic Mellitus (DM), a chronic metabolic disorder, is amajor public health problem due to its associated complica-tions [1]. One of the major complications of DM is DR,which is an important cause of preventable blindness. Inthe United States, DR is the leading cause of blindness forpatients with age of 20 to 64 and accounts for about 12% ofall new cases [2]. Moreover, 80% of patients with DM formore than 20 years are most commonly diagnosed withDR. Nonetheless, at least 90% of new cases were shown tohave retinal structure and function restoration when propertreatments were applied [3].
DR is characterized by the progressive damage in the ret-inal microvasculature. It can be classified into nonprolifera-tive DR (NPDR) and proliferation DR (PDR) [4, 5]. NPDR
is featured with intraretinal microvasculature changes [6]and can be further divided into mild, moderate, and severestages that may associate with diabetic macular edema(DME) [7]. PDR involves the formation and growth of newblood vessels (retinal neovascularization) in low oxygen con-dition [6]. Thus, the newly formed blood vessels are fragileand without timely treatment may lead to vision loss. In mostcases, DR is also featured with increased vascular permeabil-ity, leading to fluid accumulation and retinal hemorrhages inthe macula, all of which referred to DME [8–10].
There are three major treatments of DR, such as laser sur-gery, pharmacotherapy, and vitrectomy, which are effectiveto reduce vision impairment [11]. Intraocular pharmacother-apy, particularly applying anti-inflammatory (corticoste-roids) and anti-angiogenic agents (VEGF inhibitors), hasbecome the most preferred therapy for DR [12]. The
HindawiJournal of OphthalmologyVolume 2018, Article ID 1694187, 13 pageshttps://doi.org/10.1155/2018/1694187
advantage of intraocular pharmacotherapy is that multipleintraocular injections decrease the treatment burden of somepatients, but others with chronic DME may require intensivelonger-term therapy. Recent studies showing that intravitrealcorticosteroid and anti-VEGF agents have promising resultsin treating the progression of PDR and DME, which lead toincreased use of these agents. However, its short-durationeffects and severe side effects limit its use [13]. Indirectly,these agents are unable to substitute the panretinal photoco-agulation, which provides longer effects and effectiveness inpreventing vision loss in the late stages of DR. Therefore,pharmacotherapy is still considered an adjunct treatment topanretinal photocoagulation. Further searching for a betterpharmacotherapy has led to the discovery of recentlyapproved anti-VEGF drugs (aflibercept) and corticosteroids(dexamethasone and fluocinolone inserts) [14, 15]. Thesedrugs provide longer durations of action. Further, danazoland minocycline (oral medications) and loteprednol (modi-fied topical drugs) require daily administration, thus decreas-ing the necessity of patients to visit physicians [12]. Inaddition, drugs administered using the intravitreal route aseither monotherapy or combination therapy in targetingdifferent biochemical pathways that induce DR are alsodeveloped. However, their durability and effectiveness needfurther monitoring [12]. Therefore, longer action drugs,sustained drug delivery systems of corticosteroids and anti-VEGF, and encapsulated cell technology may furtherdecrease treatment burden, though regulatory approval maynot occur for at least 5 years.
2. Methodology
The literature search was conducted on PubMed with nolimitation on language or year of publication. The reviewfocuses on the clinically used drugs/proteins along with abrief background on the path physiology of DR. The majorfocus of this review revolves around current and newdrugs/proteins, drug delivery system, drug delivery devices,and potential encapsulated cell technology in treating DR.In each category, major advances are discussed along withthe possible solutions.
3. Pathophysiology
3.1. Growth Hormone. The exact mechanism of how DMcauses DR is unclear. However, several theories have beenpostulated to explain the typical course and history of DR[16]. One of the theories is growth hormone. Growthhormone has been demonstrated to affect the developmentand progression of DR. Women diagnosed with hemorrhagicnecrosis of the pituitary gland, called Sheehan syndrome, areassociated with a reversible DR [17]. In 1950, pituitary abla-tion was used to treat or prevent DR; however, this practice isconsidered controversial and has been abandoned due tomany systemic complications and the discovery of lasersurgery [17]. Besides, patients with hypopituitarism werediagnosed with DR [17].
3.2. Platelets and Blood Viscosity. DM patients are frequentlyassociated with retinal ischemia, which is a risk factor tocontribute to the development of DR. DR patients with reti-nal ischemia are found to have various hematologic abnor-malities, including increased red blood cell aggregation,decreased red blood cell deformability, increased plateletaggregation, and adhesion. Further, the patients are proneto have sluggish circulation, endothelial damage, and focalcapillary occlusion [18].
3.3. Aldose Reductase (AR) and Vasoproliferative Factors.DMis caused by the abnormality in the glucose metabolism,mostly due to the decreased levels or activity of insulin. Bothstructural and physiologic effects are induced by increasedlevels of glucose, causing the retinal capillary to be function-ally and anatomically abnormal [19]. The effects of excessglucose on retinal capillary are due to the biochemicalchanges in the polyol (or aldose reductase (AR)) pathway[20]. In the polyol pathway, glucose is metabolized intosorbitol. Accumulation of sorbitol results in intramural peri-cytes of retinal capillaries losing their primary function, forexample, auto regulation of retinal capillaries [20]. Eventu-ally, this lead to weakness and saccular outpouching of thecapillary walls (or termed microaneurysms). Microaneur-ysms are the earliest detectable symptoms for DR. Rupturedmicroaneurysms cause retinal hemorrhage. Subsequently,increased permeability of the vessels leads to retinal thicken-ing due to leakage of fluids and proteinaceous substances[18]. A diminution in central vision can be involved in retinalthickening happens in the macula [20]. Nailfold video capil-laroscopy can be used to examine the retinal damage-relatedcapillary changes, indicating a generalized microvesselinvolvement in both type 1 and 2 diabetic patients [18, 21].
3.4. Macular Edema. Macular edema is one of the mostcommon of vision loss. It is usually detected in patients withNDPR, and it may also complicate the patients with PDR.The development of macular edema is caused by theincreased levels of diacylglycerol during the shunting ofexcess glucose. Increased levels of diacylglycerol activatethe protein kinase C, leading to fluid leakage and retinalthickening [22, 23].
3.5. Hypoxia. As the disease progresses, the closure of theretinal capillaries induces hypoxia (low oxygen perfusion).Further, infarction of the nerve fiber layer forms cotton-wool spots, with stasis in axoplasmic flow association [20].Various compensatory mechanisms are activated by exten-sive hypoxia to provide sufficient oxygen to tissues. Increas-ing hypoxia causes venous caliber abnormalities, such asvenous beading, loops, and ablation, which can be observedin the areas of capillary nonperfusion. This observation sub-sequently leads to intraretinal microvascular abnormalities,featured with the growth of new vessels and remodeling ofpreexisting vessels via endothelial cell proliferation [20].
3.6. Neovascularisation. Persistent retinal ischemia results inthe production of vasoproliferative factors to stimulate newvessel formation. Firstly, the extracellular matrix of the retinais first broken down by the proteases followed by growth of
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new vessels from the retinal venules and penetrates theinternal limiting membrane and form capillary networkbetween the inner surface of the retina and the posterior hya-loid face [20]. Nocturnal intermittent hypoxia, a risk factorfor iris and/or angle neovascularization, arises from sleep-disordered breathing in patients with PDR [24]. Neovascu-larization can be found at the borders of perfused andnonperfused retina and most commonly along with the vas-cular arcades and at the optic nerve head [20]. The newlyformed vessels are fragile and easily disrupted by vitreoustraction, resulting in hemorrhage in the vitreous cavity orpreretinal space [20]. In addition, these new vessels areinitially associated with a small amount of fibroglial tissueformation, which increases as the density of the neovascularfrond increases [16]. Gradually, the vessels may regress andonly the networks of avascular fibrous and tissue can beadherent on the retinal and posterior hyaloid face. Thetractional forces applied on the retina via these fibroglialconnections, may cause retinal edema, retinal heterotropia,and retinal detachment and retinal tear formation with sub-sequent detachment [20].
4. Therapeutic Approaches and Their CurrentDelivery System
The pharmacotherapy for the treatment of DR is mainlyresolved around corticosteroid therapy and anti-VEGFagents. Besides, the potential plant-based drugs, vitreolyticagents, systemic agents such as hypoglycemic, hypolipid-emic, and antihypertensive, and pluripotent stem cells tech-nology in treating the progression of DR are also discussed.The background of the delivery system for these existing ornewly discovered drugs is also briefly discussed.
4.1. Anti-Inflammatory Agents. Corticosteroids have beenreported to possess high anti-inflammatory and antiangio-genesis activities [13] by modulating the various proinflam-matory mediators, such as tumor necrosis factor-alpha(TNF-α), interleukin-1β (IL-1β), and VEGF. These media-tors are upregulated during DR progression [13]. The pri-mary design for delivering corticosteroids is via directioninjection (intravitreal route) in order to avoid the blood-retinal barrier limitations to reach the target site. Corticoste-roid therapy has been widely used as a treatment option forDME and DR; however, their use is limited due to theshort-duration effects. Moreover, direct intravitreal injec-tions were reported to have severe side effects, such as cata-ract and elevation of IOP [25]. Other less common sideeffects of these injections include retinal detachment, vitre-ous hemorrhage, and endophthalmitis [26, 27]. Nonetheless,the systemic use of corticosteroid therapy can be an effectiveadjunct to laser photocoagulation to treat DME and DR, aswell as improve the condition of best-corrected visual acuity(BCVA) [28].
Intravitreal triamcinolone acetonide (IVTA) has beenreported to have potent anti-inflammatory activity andimprove the condition of DME and age-related maculardegeneration (AMD) [29–33]. The effect of IVTA is transientand possibly last for three months. Thus, multiple injections
of IVTA are required in order to maintain its effectiveness.IVTA is also capable of reducing PDR due to its potent anti-angiogenic effects [34]. Thus far, the United States Foodand Drug Administration (FDA) has approved two IVTApreservative-free injections with a recommended doseusage, including triesence (40mg/ml, Alcon) and trivaris(80mg/ml, Allergan) to alleviate the condition of nonin-fectious endophthalmitis and other complications [34].The effectiveness of lower doses of trivaris (1 and 4mg) wastested by the DR clinical research (DRCR) network in a large,multicenter randomized clinical trial for the treatment ofmacular edema. In comparison to trivaris, treatment ofmacular photocoagulation showed improved BCVA andfewer complications [13]. However, trivaris treatment causeda lower rate of endophthalmitis (0.05%) in patients enrolledthroughout the three years of follow-up [35]. Next, trivarisadministered at three months demonstrated improvedBCVA, but no effects at a longer period of treatment as sug-gested by many randomized clinical trials [36]. In this regard,the development of novel IVTA delivery devices that arereleased in a small quantity in a sustained system is required.
4.2. Corticosteroid Therapy with Sustained Delivery System.Sustained-release corticosteroid therapy has been developedto treat chronic DR and also reduced the associated adverseeffects. One of such delivery systems for use in DME is triam-cinolone acetonide (TA) implant (I-vation®). I-vation iscurrently completed in phase I clinical trial for the long-term treatment of DME while the second clinical trial ofTA implant is still under planning [37, 38]. This drug deliv-ery device is made of biodegradable polymers which degradeslowly for a period of time and bypass the risk of secondarysurgical complications upon removal compared to nonbiode-gradable devices [37].
Another sustained drug delivery system is fluocinoloneacetonide nonbiodegradable intravitreal insert (Iluvien®, Ali-mera Sciences). Iluvien is designed to release fluocinolone forup to three years. Interestingly, this device is very small, whichallows direct injection to the back of the eye with a self-sealinghole. It hasbeen reportedbyaFAMEstudy that lowdoseof Ilu-vien inserted (0.19mg per day) showed improved BCVAcompared to higher dose [14, 15, 39]. Currently, Iluvien is stillunder investigation by FDA to approve its application tothe market [13]. In comparison, another fluocinolone acet-onide intravitreal implant, Retisert® (Bausch and Lomb), isapproved by FDA for the treatment of chronic, noninfec-tious uveitis. However, its treatment caused severe cataractand glaucoma in a phase III clinical trial [14, 15].
Besides, FDA has also approved Ozurdex (allergen),which is a sustained release of biodegradable dexamethasoneintravitreal implant for the treatment of macular edema. Astudy that carried out in 2007 discovered that higher doseof dexamethasone (700μg) statistically improved that BCVAand well-tolerated by patients at three months compared tolow dose (350μg). However, there was no further improve-ment in BCVA at six months and both doses caused IOPelevation [40, 41].
Next, Cortiject implant (NOVA63035; Novagali Pharma)is a tissue-activated proprietary corticosteroid prodrug that
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available in a preservative- and solvent-free emulsion. Asingle injection of the emulsion provides the efficacy forabout six to nine months period. At the retina level, the pro-drug is converted into active drug format. Currently,NOVA63035 is under phase I clinical trial with differentsettings of open-label and dose-escalation to test its safetyand tolerability in patients diagnosed with DME [42].
Lastly, Verisome delivery system is also used for sustain-release of corticosteroids. This device is biodegradable andprovides a controlled, extended release of drug in a titratableperiod for up to one year. Once released via a standard 30-gauge needle, the liquid coalesces into s spherule in the vitre-ous. Verisome technology is currently used in the clinicaltrials for the sustained-release delivery of TA (IBI-20089)[13, 43]. A single intravitreal injection of Verisome-delivered IBI-20089 was tested in phase I and II clinical trialsfor patients with cystoids macular edema associated with ret-inal vein occlusions (RVO) using two doses, with 25μl dosedesigned for six months period and 50μl dose designed forone year [44]. The 25μl dose was incorporated with a lowerdose of triamcinolone (6.9mg) while 50μl doses administeredwith a higher dose of triamcinolone (13.8mg) [44]. The resultsshowed that the patients were well-tolerated with Verisomewithout any related adverse effects. The lower dose of triam-cinolone showed evidence of controlled release efficacy, withgreater control was demonstrated with higher dose [44].
4.3. Other Nonsteroidal Anti-Inflammatory Agents. There areother nonsteroidal anti-inflammatory agents that have beenapproved by FDA to treat DR and DME. One of them isnepafenac (Nevanac®, Alcon), which is a topical nonsteroidaldrug that has shown great efficacy to treat DME [45]. How-ever, nepafenac testing in clinical trials is under way. Next,etanercept (Enbrel®, Amgen Inc., and Wyeth) is a recombi-nant fusion protein that targets TNF-α. It is approved byFDA to treat psoriasis [46]. It has shown that patients withrefractory DME treated with intravitreal etanercept did notshow any improvements [47]. Another, TNF-α antagonistis infliximab (Remicade®, Centocor) and it is used to treatCrohn’s disease. Systemic treatment of DME with intravitrealinfliximab injection achieved anatomic and functionalimprovement was achieved [48].
4.4. Antiangiogenic Agents. Antiangiogenic agents have beenshown to effectively treat PDR and DME in addition to cor-ticosteroid therapy. More novel and specific anti-angiogenicagents were discovered to solve the DME-associated vascularleakage and neovascularization. These antiangiogenic agent’sprimary targets the subfamily protein, VEGF, in which itsover-expression plays a crucial role in the progression ofDR and AMD [13]. Nonetheless, laser photocoagulation isstill considered gold standard therapy for PDR; with anti-VEGF agents used as its adjunct treatment to reduce theadverse effects.
Bevacizumab (Avastin®, Genentech) is a full-lengthhumanized antibody that targets all subtypes of VEGF [49].Intravitreal injection of Avastin has led to the reduction ofvascular permeability, and retinal and choroidal neovascular-isation, all of which are precursor lesions for developing PDR
and AMD [50–53]. In addition, intravitreal Avastin therapywas reported to reduce iris and retinal neovascularization[54]. However, the effect is short as recurrence of neovascu-larization was found after two weeks [54]. After all, Avastinis now widely used as a clinical adjunct to laser photocoagu-lation to treat patients with PDR [55, 56]. In 2006, FDA hasapproved ranibizumab (Lucentis®, Genentech Inc.), whichis a recombinant humanized antibody fragment used totarget VEGF-A to treat exudative AMD [57, 58]. In 2010,Lucentis was approved by FDA for the treatment of MEfollowing RVO after evaluating its safety and efficacy profilesby BRAVO and CRUISE studies. In comparison withpatients receiving sham injections, the patients treated withLucentis met the primary endpoint of mean change fromthe baseline in BCVA at six months. The patients in theBRAVO study treated with Lucentis had a mean gain of18.3 letters compared to 7.3 letters in the control patients atsix months. A similar result pattern was observed in theCRUISE study, in which treated patients had a mean gainof 14.9 letters while control patients had 0.8 letters [59, 60].Moreover, Lucentis was found to meet the primary endpointof one of the two-phase III clinical trials (called RISE study)in January 2011 [13].
Another recombinant protein is VEGF trap-eye (afliber-cept, EYLEA®, Regeneron Pharmaceuticals Inc., and BayerHealthCare Pharmaceuticals) which fuse both human VEGFreceptors 1 and 2 extracellular domains and a Fc portionof human IgG1 that binds all subtypes of VEGF-A alongwith the related placental growth factor. It has been testedin VIEW1 and VIEW2 clinical trials that patients werefound to be well-tolerated with intravitreal VEGF trap-eye injection one month after Lucentis therapy [61, 62].VEGF trap-eye is currently under marketing approval byEuropean Medicines Agency for the treatment of wet mac-ular degeneration [13].
JSM6427, an antiangiogenic compound developed byGerman biopharmaceutical company (Jerini AG) has beenshown positive results in reducing DR. Sustained release ofJSM6427 by using an intraocular implanted osmotic pumpfor an extended period of six months. Currently, JSM6427is under phase I clinical trial [63].
TG100801 is a topical prodrug that may be effective intreating retinal disorders and it can be contemporary usedwith other approved products. It has been shown that topicaladministration of TG10001 alleviated the retinal changes,such as retinal leakage, angiogenesis, and inflammation thatmediated by VEGF [64]. Once released, it converts to activedrug, TG100572, which was reported to treat DR and wetmacular degeneration by overcoming neovascularizationand inflammation [65].
ATG3, a topical drop developed by CoMentis Inc. anddesigned to penetrate into retina and choroid effectively.ATG3 targets angiogenesis-mediated nicotinic acetylcholinereceptor pathway. It is currently under phase III clinical trialfor its use to treat neovascular AMD.Well-tolerability and nosystemic sides effects were observed in 80 healthy controlstreated with single- and multiple-dose ascending regimensfor up to 14 days in a randomized, double-masked,placebo-controlled phase I study [65].
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Lastly, an orally administered antiangiogenic drug,pazopanib was developed by GlaxoSmithKline. This drug isdesigned to target VEGF receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and c-kit. Cur-rently, it is under phase III clinical trials to test its safety,efficacy, and well-tolerability [66, 67].
4.5. Vitreous Agents. Vitrase (hyaluronidase ovine, ISTAPharmaceuticals Inc.) is the first and only pure, preserva-tive-free, thimerosal-free, ovine hyaluronidase. FDA hasapproved its use as a spreading agent. It is currently in aphase III clinical study to test its capability in clearing vitre-ous hemorrhage from PDR [68].
Microplasmin is another vitreous agent and administeredvia intravitreal injection. It has been reported to treat DMEand PDR by inducing posterior vitreous detachment. Forexample, ThromboGenics NV (Belgium) has carried out arandomized, double-masked, sham-injection controlled,dose-ascending clinical trial to compare the effects of multi-ple doses of intravitreal microplasmin for treatment ofpatients with DME compared to control patients. The findingshowed that microplasmin has the ability to induce vitreousdetachment by greatly reducing retinal neovascularization[69, 70]. Moreover, microplasmin was reported to cure focalvitreomacular adhesion as tested in two MIVI-TRUST phaseIII clinical trials. The trials demonstrated that microplasmincan resolve vitreomacular adhesion and cure full thicknessmacular hole and vision impairments and that it is safe andwell-tolerated [71, 72].
4.6. The Potential Use of Systemic Agents to Treat DR. Manysystemic agents that are primarily used to treat dyslipid-emia and hypertension in diabetic patients were found toreduce the progression of DR. However, their mechanismsof action in treating DR need further investigations pre-clinically and clinically.
4.7. Hypoglycemic Agents
4.7.1. Insulin Therapy. Insulin is used to primarily inhibit theprogression of long-term diabetic complications. Manystudies have reported that a good glycemic control is an effec-tive treatment option to delay DR progression [73]. Forexample, Diabetes Control and Complications Trial (DCCT)demonstrated that intensive insulin therapy can induce reti-nal proangiogenic effects while intensive glycemic controlimproved this condition [74].
4.7.2. Thiazolidinediones. Thiazolidinediones are orallyadministered hypoglycemic agents, which can be used as amonotherapy or in use with other hypoglycemic agents.Extensive use of thiazolidinediones can improve the glycemiccontrol by decreasing 1% of HbA1C values [73]. The mecha-nism of action of thiazolidinediones in improving glycemiccontrol and delaying the progression of DR via its antiangio-genic effect by inhibiting the activation of peroxisomeproliferator-activated receptor-γ (PPAR-γ). PPAR-γ is atranscription factor that regulates the expression of geneslocated in the adipose tissue and retina [75].
4.7.3. Biguanides. Biguanides, also known as metformin, is aproven hypoglycemic agent and has cardioprotective effects.It has been shown to process potent anti-inflammatory andantiangiogenic activities by decreasing the concentration ofplasminogen activator inhibitor 1 and increasing the concen-tration of fibrinolytic activity [76, 77].
4.8. Hypolipidemic Agents
4.8.1. Fibrates. Fenofibrate is used to treat hyperlipidemia bymainly lowering the triglyceride levels, total and low-densitylipoprotein (LDL) cholesterol, small LDL cholesterol parti-cles, and apolipoprotein B while increasing high-density lipo-protein (HDL) cholesterol. The results obtained from theFIELD study suggested that fenofibrate is a potential adjunctto photocoagulation. Besides, the effect of fenofibrate alsoacts via nonlipidemic mechanisms, mainly activatingPPAR-α for DR prevention. Activation of PPAR-α mediatedby fenofibrate led to inhibition of VEGFR2 expression andneovascularization in human umbilical endothelial cells.Moreover, fenofibrate also activates PPARα to induce theexpression of antioxidant enzymes, such as superoxidedismutase and glutathione peroxidase, and kills humanumbilical endothelial cells via apoptosis induction. Further,the activation of PPAR-α has been shown to have protectiveeffects on neuron cells [78–80].
4.8.2. Statins. Treatment of atorvastatin alone has beenshown to be ineffective in reducing DR, but it can reducethe need of laser treatment when use in combination asreported by Collaborative Atorvastatin Diabetes Study(CARDS) [81]. Besides, the contemporary therapy betweenfenofibrate and atorvastatin was carried by ACCORD-Eyesub study by using a modified Early Treatment DR Study(ETDRS) severity scale or laser photocoagulation for 4 weeks.The results showed 40% reduction in the relative risk of DRprogression compared with placebo. The reduction of DRprogression was due to a significant decrease in triglyceridelevels and an increase in HDL levels [81, 82].
4.9. Antihypertensive Agents
4.9.1. Angiotensin-2 Converting Enzyme Inhibitors. Bloodpressure was reported as one of the contributing factors forthe development of DR, as proper control of blood pressurereduced the development of DR in both type 1 and 2 diabeticpatients. The most common drug used to treat hypertensionin diabetic patients is angiotensin-2 converting enzyme(ACE) inhibitors because the renin-angiotensin system isalso expressed in diabetic retinal [82, 83]. Recently, RASstudy was carried out to evaluate the effect of blockingrenin-angiotensin system using either ACE inhibitor (enala-pril) or angiotensin receptor blocker (ARB) (losartan) onDR progression by examining renal and retinal morpho-logic characteristics in normotensive type 1 diabetics [84].About 65% and 70% reduction in the rate of DR progres-sion was seen after treatment with enalapril and losartan,respectively [84].
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4.9.2. Angiotensin-2 Receptor Blockers. Candesartan, an ATI-receptor blocker, was used in the Diabetic Retinopathy Can-desartan Trial (DIRECT) to evaluate its protective effectsagainst DR progression. This study was divided into threerandomized double-blind placebo-controlled parallel groupstudies, with DIRECT-Prevent 1 represented a primaryprevention study in type 1 diabetic patients without DR,DIRECT-Protect1 involving type 1 diabetic patients withDR, and lastly DIRECT-Protect2 was secondary preventionstudy that involves type 2 diabetic patients with DR.DIRECT-Prevent1 and DIRECT-Protect1 revealed that can-desartan cannot prevent DR progression while no significantreduction in the progression of DR was found in DIRECT-Protect2. Despite this fact, candesartan could treat patientswith mild DR [85].
4.9.3. Antiplatelet Agents. Platelet activation is one of the sideeffects of chronic hyperglycemia in addition to retinal inflam-mation, aggregation, and thromboxane A2 accumulation.Aspirin is an antiplatelet agent and has been tested its effecton the progression of DR in EDTRS study. This studyshowed that aspirin treatment did not have any effects ondisease progression or on the rates of vitreous hemorrhage.In addition, the possible effect of aspirin in slowing the pro-gression of DR was observed when it used with dipyridamole[86, 87]. Moreover, Dipyridamole, Aspirin, Microangiopathyof Diabetes (DAMAD) study further showed that combina-tion use of aspirin and dipyridamole caused a significantreduction in microaneurysms formation [86].
4.10. Other Potential Systemic Agents
4.10.1. Ruboxistaurin. Ruboxistaurin (Arxxant®, Eli Lilly andCompany) is a new class of compounds that is considered aninvestigational agent to treat NPDR. It has been shown totreat moderate to severe NPDR by reducing the overactiva-tion of protein kinase C beta, which is involved in the patho-genesis of DR [88, 89]. Besides, it was reported to reduce theprogression of DME and rates of vision loss in patients withDME [90, 91].
4.10.2. Somatostatin Derivatives. Somatostatin possessesantiangiogenic activity in addition to its function as endoge-nous growth hormone inhibitor. Octreotide (Sandostatin®,Novartis) is an analog of somatostatin, which has been usedas an anticancer drug for acromegaly, carcinoid tumors,and vasoactive intestinal peptide tumors. Treatment ofoctreotide decreased the rates of progression to PDR, vitre-ous hemorrhage, and the need for vitrectomy in patients withsevere NPDR [92, 93].
4.10.3. Potential Plant-Based Drugs. Plant-based drugs havealso shown promising results in treating DR. The reasons ofusing plant-based drugs to combat DR disease are due totheir safety, ability to produce hypoglycemic effects, and reti-noprotective effect. One of the biochemical pathways thatleads to DR induction is polyol pathway activation. Thispathway metabolizes excess glucose in diabetes. The mainenzyme in this pathway is aldoreductase (AR), which func-tions to reduce glucose in the retina to sorbitol using
nicotinamide adenine dinucleotide phosphate (NADPH) asa cofactor [94, 95]. Since NADPH is consumed in this path-way, leading to lower antioxidant activity in retinal cells asNADPH is also required to act as a cofactor to produceintracellular glutathione. Decreased reduced glutathioneleads to limited protective against oxidative stress. Gener-ated sorbitol is impermeable to cellular membrane; thus,it accumulates in the cells before converting to fructose viaslow metabolism [94, 95]. The remaining unconverted sorbi-tol has multiple damages to retinal cells, including osmoticdamage [94, 95]. A few studies demonstrated the importantrole of polyol pathway in the pathogenesis of DR, in whichAR inhibitors significantly reduced the incidence and sever-ity of diabetic retinal lesions in galactose-fed animals [96–98]. During the activation of polyol pathway leading to DR,retinal ganglionic and endothelial cells are prone to damagebecause they are endowed with AR enzyme [6].
There are many AR inhibitors derived from plants, suchas Ocimum sanctum, Tinospora cordifolia, Azardiractaindica, Ganoderma lucidum, and so forth Ocimum sanctumexerts its protective effect against DR when in use withvitamin E [99]. Tinospora cordifolia protects against DR bypreventing retinal oxidative stress mediated by overexpres-sion of proangiogenic and proinflammatory mediators[100]. Ganoderma lucidum has a protective effect on theretina from oxidative damage [101].
One of the plant-derived compounds is curcumin, whichhas been reported to prevent DR progression in a rat modelby inhibiting the upregulation of retinal VEGF levels [102].Further, curcumin was able to prevent the basement mem-brane from becoming thickened via antioxidant and anti-inflammatory mechanisms in the retina of treated rat [103].Pycnogenol® is an extract from the bark of the maritimepine tree. This extract has potent antioxidant and anti-inflammatory activities, resulting in its use in the manage-ment of DR [103, 104]. Besides, chronic oral administra-tion of genistein has been shown to prevent retinalvascular leakage in a rat model, possibly via the good tyro-sine kinase inhibitory activity [105]. Green tea has alsoshown the good effect on DR, in which drinking greentea have proved to reduce the onset and incidence of DR[106, 107]. Hesperetin has also shown to have a preventiveeffect against DR [108]. Other compounds, such as querce-tin and rosmarinic acid was showed to reduce DR by pre-venting angiogenesis via its antioxidant activity [109, 110].
4.10.4. Possibility of Patient-Specific Photoreceptor CellReplacement. Vision impairments are associated with thedeath of the light sensing photoreceptors cells of the outerneural retinal [111]. Transplantation-based photoreceptorcells replacement might be an attractive strategy to restorethe retinal function, as the inner layers of the neural reti-nal of the majority of retinal degenerative patients con-necting photoreceptor cells to the brain remained intact[112]. Moreover, the retinal does not have inhibitory myelin-associated proteins found in other central nervous systemcompartments [113].
A few cell types have been tested in the retinal degenera-tive models to restore the retinal functions. Cell types tested
6 Journal of Ophthalmology
include retinal progenitor cells isolated from developingfetuses, and mature photoreceptor cells derived from post-mortem donor eyes [114–117]. Nonetheless, the post-mitoticphotoreceptor precursor cells were found have the greatestcapacity to survive, integrate with the remaining retinal cellsto differentiate into mature photoreceptor cells upon post-transplantation [115, 118–122]. Further, recent advances inpluripotent stem cell technology enable researchers togenerate photoreceptor precursor cells, which are difficult toobtain from human donor tissue due to the difference in celldifferentiation and post-mortem degradation [111]. Underthe controlled condition, functional photoreceptor precursorswere able toderive frompluripotent stemcells and restored theretinal structure and function of the animal following trans-plantation [118, 120, 121, 123–125].
Recently, there are many debates about the suitability andclinical relevant of using either embryonic stem cell- (ESC-)and induced pluripotent stem cell- (iPSC-) derived retinalcells for transplantation [111]. The ethical concerns associ-ated with ESC revolve around harvesting embryonic tissuesfor ESCs generation and immunological issue upon trans-plantation into unmatched recipients [126, 127]. It has beenreported that patients transplanted with ESC-derived photo-receptor precursor cells require prolonged immunosuppres-sive therapy [128]. Nonetheless, ESCs can be generated intoa sufficient quantity to treat many patients. Comparatively,the iPSC strategy allows the patients transplanted with genet-ically normal, immunological-match retinal cells when usewith genome editing [129]. However, the iPSC method hasits own drawbacks that autologous iPSC must be generatedand validated per patient basis, resulting in this method beingcostly and requiring many skilled personnel per treatedpatient [111]. Interestingly, xeno-free and current GoodManufacturing Practice- (cGMP-) compatible iPSC proto-cols have been developed, which enhances the applicationof the iPSC method in nonprofit academic centers to treatregional patients [111].
Mesenchymal stem cells (MSCs) have been derived frombone marrow, cord blood, and peripheral blood as well asfrom other sources creates a high impact on cell therapy ineye diseases [130]. Adult bone marrowMSC which is positivefor CD90 can partially differentiate into photoreceptors bothin in vivo and in vitro and it is found to be neuroprotectivein rat glaucoma model [131]. Adipose stromal cells (ASCs)have also gained increased attention because of its ability topreserve the transparency as well as it could get modified intofunctional keratocytes which suggests that it could be used assource for stromal regeneration in diseased corneas [132].Intravitreal injection of ASC in streptozotocin- (STZ-)induced chronic diabetic model paired with host vasculaturewhich suggests the possible pericyte replacement [133]. Itwas also shown to secrete Angiopoietin-1 (Ang-1) in atime-dependent manner, which is downregulated in DRespecially when grown in culture medium containing vascu-lar growth factors was found to promote reendothelialization[134]. It was also shown to improve blood glucose levels andmaintain blood-retinal-barrier in STZ-induced DR rat model[135]. It was also shown to secrete several antiapoptotic, che-motactic, and anti-inflammatory proteins which were found
to mediate beneficial effects of MSCs [136]. All these findingsfrom rodents suggest that stem cells isolated from adipose tis-sue can be used as vehicle for the long term and sustaineddelivery of drugs to eye tissues and can replace the infectedtissue with stem cells which might prove their beneficialeffects [137]. Although the evidences are supportive to pro-vide therapeutic approach for testing in human with retinaldiseases, but further studies are warranted to specificallyidentify the role of these proteins in DR.
4.11. Antioxidants as Potent Therapeutic Agent. Partial resto-ration of diminished pericytes in retinal vessels is closelyassociated with administration of antioxidant treatment indiabetic rats [138]. During DR, oxidative stress has beenclosely linked to apoptosis of retinal cells and it leads tomicrovascular cell loss [139].
The antioxidant pharmacotherapy uses antioxidantenzymes, drug formulations, biogenic elements, andcompounds with antioxidant activity [140]. The treatmentcriteria involving both intake of antioxidants through dietand supplementation. This procedure involves carefulanalysis of data and dosage of administration necessary toalleviate complications of diabetes and its side effects. N-acetylcysteine (NAC), vitamin C, and α-lipoic acid has beenfound to be effective in reducing diabetic complications.These may be administered through dietary intake orthrough ingestion of natural antioxidants both of whichmight be effective in therapy [141–143].
Clinical studies carried out in type I diabetic patientsshowed that high dose of vitamin Ewas found to restore bloodflow in retina and prevent the loss of pericytes in diabetic ratsthrough lipid peroxidation of the membrane [144, 145].Vitamin C causes reduction in retinal neovascularizationthrough suppression of superoxide production [146].
Calcium dobesilate has showed to decrease permeabilityof retina and reduce the expression of VEGF in diabetic rats.Although it has been widely used in many countries, theexact mechanism of action needs to be explored [147, 148].Caffeic acid is an antiangiogenic agent which suppressesROS production and VEGF expression in cells of the retina[149]. Lipoic acid attenuates apoptosis of rat retinal cellsand prevents increase in nitrotyrosine levels and NF-κB acti-vation. It is also found to decrease the levels of VEGF andoxidation of proteins in retinal cells [150]. Rosmarinic acidsignificantly inhibits the retinal cell proliferation and showedto be nontoxic [151]. Benfotiamine, pyridoxamine, nicanar-tine, zinc, selenium, pycnogenol, curcumin, taurine, andgreen tea have been found to have various free radical scav-enging properties and has been useful in treatment of DR.Benfotiamine, inhibits MnSOD, via blocking of the pathwaysinvolved in hyperglycemia [152]. Nicanartine, is antihy-percholesterolemic which inhibits pericyte loss [153]. Zincimproved the levels of GSH in DR rats [154]. Seleniumdownregulates VEGF production in diabetic rats [155]. Tau-rine when supplemented long with selenium has been foundto reduce biochemical alterations in diabetic rats [156].Green tea polyphenols have great antioxidant potency whichhas been reported to improve SOD and GSH levels andreduce glucose levels [157]. Apart from administration or
7Journal of Ophthalmology
supplementation of individual antioxidants, a multiantioxi-dant administration might be the best therapeutic approachto treat DR [158].
Clinical trials involving compounds with the efficacy toinhibit protein kinase C and minimize oxidative stresswhich when used in combination with standard one mightpave the way to successfully treat DR [159]. However, thedosage or concentration which was found to be effective intreating DR in animals is not enough to create beneficialimpact on humans. Such discrepancies are not clear yet,but further studies are needed to determine the appropri-ate regimen [160].
The major downside in every disease condition is tomaintain an effective drug concentration at the disease sitefor appropriate period to achieve expected pharmaceuticalresponse. In such cases, use of polymeric adhesive nano-particles may enhance the efficacy of drugs. Increasingdrug retention time, slowing drug delivery, and high targetspecificity are the best therapeutic approaches for DR.Thus, an alternative for treating ocular pathology shouldprovide cost-effective treatment. Combinatorial use of theseantioxidants with nanoparticles might throw a limelight inthis devastating area.
5. Conclusion
In the current scenario, the focus of the pharmacotherapy incombating the development and progression of DR is stillmainly focused on corticosteroid therapy and anti-VEGFagents. What is the efficacy of compounds derived fromplants? In this regard, further discovery of plant-based agentsis needed. In addition, there have been some advances in thedrug delivery devices for delivering drugs/proteins; there arestill challenges to be overcome with regard to the particulatesystems. For the long-term success of DR therapeutics,research options should consider considering the developingof drug delivery systems to have an extended period of effectfor drugs/proteins, or further investigations on the possibilityof using pluripotent stem cell technology for transplantationinto DR host to restore retinal functions is needed.
Conflicts of Interest
The authors declare that there is no conflict of interestsregarding the publication of this paper.
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